U.S. patent application number 14/760549 was filed with the patent office on 2015-12-10 for process for preparing the anti-tumor agent 6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-n-methyl-1-- naphthamide and its crystalline.
The applicant listed for this patent is ADVENCHEN PHARMACEUTICALS, LLC. Invention is credited to Guoqing Paul CHEN.
Application Number | 20150353496 14/760549 |
Document ID | / |
Family ID | 51210076 |
Filed Date | 2015-12-10 |
United States Patent
Application |
20150353496 |
Kind Code |
A1 |
CHEN; Guoqing Paul |
December 10, 2015 |
Process for preparing the anti-tumor agent
6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1--
naphthamide and its crystalline
Abstract
The present invention relates a new process to synthesize
6-(7-((1-aminocyclo-propyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl--
1-naphthamide (AL3810) by deprotection of substituted benzyl
1-((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quinolin-7-yloxy)--
methyl)cyc-lopropylcarbamate (Formula I) under a diluted or weak
acidic condition. A stable crystalline form of
6-(7-((1-aminocyclo-propyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl--
1-naphthamide has also been prepared. ##STR00001##
Inventors: |
CHEN; Guoqing Paul;
(Moorpark, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ADVENCHEN PHARMACEUTICALS, LLC |
Moorpark |
CA |
US |
|
|
Family ID: |
51210076 |
Appl. No.: |
14/760549 |
Filed: |
January 17, 2014 |
PCT Filed: |
January 17, 2014 |
PCT NO: |
PCT/US14/11948 |
371 Date: |
July 13, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61754516 |
Jan 18, 2013 |
|
|
|
Current U.S.
Class: |
546/153 ; 558/49;
560/115 |
Current CPC
Class: |
C07C 271/24 20130101;
C07C 2601/02 20170501; C07C 303/26 20130101; C07D 215/233 20130101;
C07D 215/22 20130101; C07D 215/20 20130101; A61P 35/00 20180101;
C07C 231/02 20130101; C07C 269/06 20130101; C07C 309/66 20130101;
C07B 2200/13 20130101; C07C 269/00 20130101 |
International
Class: |
C07D 215/22 20060101
C07D215/22; C07C 231/02 20060101 C07C231/02; C07C 309/66 20060101
C07C309/66; C07C 269/06 20060101 C07C269/06; C07C 303/26 20060101
C07C303/26; C07D 215/20 20060101 C07D215/20; C07C 271/24 20060101
C07C271/24; C07C 269/00 20060101 C07C269/00 |
Claims
1. A process for preparing
6-(7-((1-aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-
-naphthamide (AL3810), or a pharmaceutically acceptable salt
thereof, by deprotection of substituted benzyl
1-((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quinolin-7-yl-oxy)-
methyl)cyclopropylcarbamate Formula I under a diluted or weak
acidic condition according to following chemistry scheme:
##STR00020## Wherein R.sub.1 is selected from H, halogen,
halogeno-C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, cyano or nitro; preferably selected from H,
C.sub.1-C.sub.6alkoxy, or nitro; R.sub.2 is selected from
C.sub.1-C.sub.6alkoxy, or nitro; preferably R.sub.2 is methoxy. A
diluted or weak acidic condition is selected from 5-50% TFA in
CH.sub.2Cl.sub.2 or CH.sub.3CN, 10% HCl in ethanol, 4N HCl in
dioxane, HCOOH in CH.sub.3CN or p-toluenesulfonic acid monohydrate
in CH.sub.3CN.
2. A process according to claim 1 for preparing
6-(7-((1-aminocyclo-propyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-
-naphthamide (AL3810), or a pharmaceutically acceptable salt
thereof, by deprotection of 4-methoxybenzyl
1-((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)-quinolin-7-yloxy)-
methyl)cyclo-propylcarbamate Formula II, under a condition of 10%
TFA in CH.sub.2Cl.sub.2 or a condition of 2-4 eq TSA.H2O in
CH.sub.3CN, according to following chemistry scheme:
##STR00021##
3. A compound of Formula I ##STR00022## Wherein R.sub.1 is selected
from H, halogen, halogeno-C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, cyano or nitro;
R.sub.2 is selected from C.sub.1-C.sub.6alkoxy, or nitro.
4. A method of preparing a compound having Formula I of claim 3
comprising: (a) treating formula 10 ##STR00023## at 50-120.degree.
C. with CDI and followed by reacting with CH.sub.3NH.sub.2.HCl to
give formula 11 ##STR00024## (b) treating formula 11 with formula
12 ##STR00025## i) at 100-160.degree. C. in lutidine at the
presence of DMAP to give formula 13, or; ii) at 100-160.degree. C.
in DMF or NMP with CuI and 2-picolinic acid at the presence of base
to give formula 13, or; iii) at 100-160.degree. C. in DMF or NMP
with CuI and pentanedione at the presence of base to give formula
13 ##STR00026## (c) deprotecting benzyl group by TFA in a heated
condition to give formula 14 ##STR00027## (d) treating formula 15
##STR00028## and DPPA at a heated condition and the presence of
triethylamine to give Formula III ##STR00029## (e) reducing Formula
III by NaBH.sub.4 to give Formula IV ##STR00030## (f) treating
Formula IV with CH.sub.3SO.sub.2Cl to give Formula V ##STR00031##
(g) treating Formula V with KI or NaI to give Formula VI
##STR00032## (h) i) treating formula 14 with Formula VI in acetone,
DMF or NMP with Na.sub.2CO.sub.3, Cs.sub.2CO.sub.3 or
K.sub.2CO.sub.3 at a heated condition to give Formula I, or; ii)
treating formula 14 with Formula V in acetone, DMF or NMP with
Na.sub.2CO.sub.3, Cs.sub.2CO.sub.3 or K.sub.2CO.sub.3, at the
presence of KI or NaI at a heated condition to give Formula I
Wherein R.sub.1 is selected from H, halogen,
halogeno-C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, cyano or nitro; R.sub.2 is selected from
C.sub.1-C.sub.6alkoxy, or nitro.
5. A compound of Formula II ##STR00033##
6. A method of preparing a compound having Formula II of claim 5
comprising: (a) treating formula 10 ##STR00034## at 50-120.degree.
C. with CDI and followed by reacting with CH.sub.3NH.sub.2.HCl to
give formula 11 ##STR00035## (b) treating formula 11 with formula
12 ##STR00036## i) at 100-160.degree. C. in lutidine at the
presence of DMAP to give formula 13, or; ii) at 100-160.degree. C.
in DMF or NMP with CuI and 2-picolinic acid at the presence of base
to give formula 13, or; iii) at 100-160.degree. C. in DMF or NMP
with CuI and 2,4-pentanedione at the presence of base to give
formula 13 ##STR00037## (c) deprotecting benzyl group by TFA in a
heated condition to give formula 14 ##STR00038## (d) treating
formula 15 ##STR00039## with 4-methoxybenzylalcohol and DPPA at a
heated condition and the presence of triethylamine to give formula
15b ##STR00040## (e) reducing formula 15b by NaBH4 to give formula
15c ##STR00041## (f) treating formula 15c with CH.sub.3SO.sub.2Cl
to give formula 15d ##STR00042## (g) treating formula 15d with KI
or NaI to give formula 15e ##STR00043## (h) i) treating formula 14
with formula 15e in acetone, DMF or NMP with Na.sub.2CO.sub.3,
Cs.sub.2CO.sub.3 or K.sub.2CO.sub.3 at a heated condition to give
Formula II, or; ii) treating formula 14 with formula 15d in
acetone, DMF or NMP with Na.sub.2CO.sub.3, Cs.sub.2CO.sub.3 or
K.sub.2CO.sub.3 at the presence of KI or NaI at a heated condition
to give Formula II.
7. A method of preparing a compound having Formula I of claim 3
comprising to react formula 17 ##STR00044## with ##STR00045## at a
heated condition. Wherein R.sub.1 is selected from H, halogen,
halogeno-C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, cyano or nitro; R.sub.2 is selected from
C.sub.1-C.sub.6alkoxy, or nitro.
8. A method of preparing a compound having Formula II of claim 5
comprising to react formula 17 with 4-methoxybenzylalcohol in a
refluxing toluene condition.
9. A method of preparing a compound having Formula I of claim 3
comprising: (a) treating formula 19 ##STR00046## with Formula VI
##STR00047## with a base at a heated condition to give Formula VII,
or with Formula V ##STR00048## with a base and KI or NaI at a
heated condition to give Formula VII ##STR00049## (b) hydrolizing
Formula VII under a strong basic condition to give Formula VIII
##STR00050## (c) acylating Formula VIII with CH.sub.3NH.sub.2.HCl
under heat pre-activation reaction with CDI to give Formula I.
Wherein R.sub.1 is selected from H, halogen,
halogeno-C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, cyano or nitro; R.sub.2 is selected from
C.sub.1-C.sub.6alkoxy, or nitro.
10. A method of preparing a compound having Formula II of claim 5
comprising: (a) treating formula 19 ##STR00051## with ##STR00052##
with K.sub.2CO.sub.3 at a heated condition in acetone or, with
##STR00053## with K.sub.2CO.sub.3 and KI at a heated condition in
acetone to give ethyl
6-(6-methoxy-7-((1-((4-methoxybenzyloxy)carbonylamino)-cyclopropyl)methox-
y)quinolin-4-yloxy)-1-naphthoate (b) hydrolyzing above ester with
10% NaOH in EtOH to give
6-(6-methoxy-7-((1-((4-methoxybenzyloxy)carbonylamino)cyclopropyl)methoxy-
)quinolin-4-yloxy)-1-naphthoic acid. (c) acylating above naphthoic
acid under heat pre-activation reaction with CDI followed by
addition of CH.sub.3NH.sub.2.HCl to give Formula II
11. A method of preparing a compound having Formula I of claim 3
comprising: (a) treating formula 21 ##STR00054## with Formula IV
##STR00055## by Mitsunobu reaction with DEAD or DIAD at the
presence of a Mitsunobu ligand to give Formula IX ##STR00056## (b)
treating formula IX with formula 11 ##STR00057## i) at
100-160.degree. C. in lutidine at the presence of DMAP to give
Formula I, or; ii) at 100-160.degree. C. in DMF or NMP with CuI and
2-picolinic acid at the presence of base to give Formula I, or;
iii) at 100-160.degree. C. in DMF or NMP with CuI and pentanedione
at the presence of base to give Formula I. Wherein R.sub.1 is
selected from H, halogen, halogeno-C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6 alkoxy, cyano or nitro;
R.sub.2 is selected from C.sub.1-C.sub.6 alkoxy, or nitro.
12. A method of preparing a compound having Formula II of claim 5
comprising: (a) treating formula 21 ##STR00058## with formula 15c
##STR00059## by Mitsunobu reaction with DEAD at the presence of
triphenylphosphine to give formula 21b ##STR00060## (b) treating
formula 21b with formula 11 ##STR00061## i) at 120.degree. C. in
lutidine at the presence of DMAP to give Formula II, or; ii) at
120.degree. C. in DMF or NMP with CuI and 2-picolinic acid at the
presence of a base to give Formula II, or; iii) at 120.degree. C.
in DMF or NMP with CuI and 2,4-pentanedione at the presence of a
base to give Formula II.
13. An intermediate compound selected from the following compounds
having Formula III, Formula IV, Formula V, Formula VI, Formula VII,
Formula VIII or Formula IX: ##STR00062## ##STR00063## Wherein
R.sub.1 is selected from H, halogen, halogeno-C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, cyano or nitro;
R.sub.2 is selected from C.sub.1-C.sub.6alkoxy, or nitro.
14. An intermediate compound selected from the following compounds:
##STR00064## ethyl
6-(6-methoxy-7-((1-((4-methoxybenzyloxyl)carbonylamino)cyclopropyl)methox-
y)-quinolin-4-yloxy)-1-naphthoate
6-(6-methoxy-7-((1-((4-methoxybenzyloxyl)carbonylamino)cyclopropyl)methox-
y)-quinolin-4-yloxy)-1-naphthoic acid 4-methoxybenzyl
1-((4-chloro-6-methoxyquinolin-7-yloxy)methyl)cyclopropylcarbamate
15. A crystalline form of
6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1--
naphthamide exhibiting at least one of a melting point at
185.degree. C.-205.degree. C.; a no observable endotherm DSC from
about 40.degree. C. to about 185.degree. C.; an observable
endotherm DSC from about 185.degree. C. to about 210.degree. C.; a
TGA themogram that doesn't exhibit significant weight loss until at
210.degree. C. to 250.degree. C.; a XRPD graph having 20-40
characteristic peaks.
16. A crystalline form of
6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1--
naphthamide according claim 15 exhibiting at least one of a melting
point at 192.degree. C.-196.degree. C.; a DSC having observable
endotherm from about 193.degree. C.-202.degree. C.; a TGA
demonstrating as an unsolvated material with weight loss at about
230.degree. C.; a XRPD having pattern compromising characteristic
peaks with all intensity % expressed in d values and angles as
follows: TABLE-US-00003 NO. Angle d value 1 10.429 8.476 2 11.811
7.487 3 12.287 7.198 4 13.293 6.655 5 13.658 6.478 6 15.778 5.612 7
16.186 5.472 8 16.682 5.310 9 17.102 5.181 10 17.907 4.949 11
18.631 4.759 12 19.027 4.661 13 19.847 4.470 14 20.545 4.320 15
21.214 4.185 16 21.843 4.066 17 22.058 4.026 18 22.682 3.917 19
23.453 3.790 20 24.065 3.695 21 24.708 3.600 22 25.072 3.549 23
25.435 3.499 24 25.886 3.439 25 27.929 3.192 26 28.420 3.138 27
29.137 3.062 28 30.331 2.944 29 31.172 2.867 30 31.803 2.811 31
32.613 2.743 32 37.959 2.369 33 39.470 2.281
17. A crystalline form of
6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1--
naphthamide according claim 15 exhibiting at least one of a melting
point at 192.degree. C.-196.degree. C.; a DSC having observable
endotherm from about 193.degree. C.-202.degree. C.; a TGA
demonstrating as an unsolvated material with weight loss at about
230.degree. C.; a XRPD having pattern compromising characteristic
peaks with intensity % greater than 10% expressed in d values and
angles as follows: TABLE-US-00004 NO. Angle d value 1 10.429 8.476
4 13.293 6.655 6 15.778 5.612 7 16.186 5.472 10 17.907 4.949 12
19.027 4.661 13 19.847 4.470 15 21.214 4.185 16 21.843 4.066 17
22.058 4.026 18 22.682 3.917 19 23.453 3.790 20 24.065 3.695 21
24.708 3.600 22 25.072 3.549 23 25.435 3.499 25 27.929 3.192 31
32.613 2.743 33 39.470 2.281
18. A crystalline form of
6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1--
naphthamide according claim 15 is recrystallized from isopropanol.
Description
[0001] This application claims the benefit of U.S. Provisional
Applications 61/754,516 filed on Jan. 18, 2013
FIELD OF THE INVENTION
[0002] The present invention relates a new process to synthesize
6-(7-((1-aminocyclo-propyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl--
1-naphthamide (AL3810) by deprotection of substituted benzyl
1-((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quinolin-7-yloxy)--
methyl)cyclopropylcarbamate (Formula I) under a diluted or weak
acidic condition. A stable crystalline form of
6-(7-((1-aminocyclo-propyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl--
1-naphthamide has also been prepared.
BACKGROUND OF THE INVENTION
[0003]
6-(7-((1-Aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-me-
thyl-1-naphthamide (AL3810), or a pharmaceutically acceptable salt
(such as hydrochloride salt) thereof, has been developed as an
anti-tumor agent also named as E3810 and lucitanib, see "Journal of
Cellular and Molecular Medicine vol. 16 issue 10 Oct. 2012. p.
2321-2330", "Cancer Res Feb. 15, 2011 vol. 71 no. 4 1396-1405".
[0004] This compound has been structurally disclosed in
WO2008112408 as an agiogenesis inhibitor with few preparation
methods. A new process has been disclosed in WO2010105761 with the
removal of use of sodium azide. Both above disclosed processes have
involved a deprotection of benzyl carbamate protected precursor by
HBr/Acetic acid solution that is a strong, fuming and high
corrosive acidic condition. No crystalline form has been
disclosed.
SUMMARY OF THE INVENTION
Abbreviations
[0005] The following abbreviations are used and have the meaning
below for ease of reference. EtOH: ethanol, MeOH: methanol, IPA:
isopropanol, EtOAc: ethyl acetate, RT: room temperature, DIPEA:
diisopropylethylamine, DCM: Dichloromethane, DMF:
N,N-dimethylformamide, NMP: 1-Methyl-2-pyrrolidinone, ACN:
acetonitrile, DEAD: Diethyl azodicarboxylate, DIAD: Diisopropyl
azodicarboxylate, CDI: 1,1'-Carbonyldiimidazole, MeNH.sub.2.HCl:
methylamine hydrochloride, TSA.H2O: 4-toluensulfonic acid
monohydrate, DMAP: 4-N,N-dimethylaminopyridine, MsCl:
methanesulfonyl chloride, THF: tetrahydrofuran, TFA:
trifluoroacetic acid, TEA: triethylamine, DPPA: diphenyl phosphoryl
azide,
eq: equivalent, g: gram, mg: milligram, ml: milliliter, min:
minutes
DEFINITIONS
[0006] The term "halogen", as used herein, unless otherwise
indicated, includes fluoro, chloro, bromo or iodo. such as fluoro
and chloro.
[0007] The term "halogeno-C.sub.1-C.sub.6alkyl", as used herein,
unless otherwise indicated, includes 1 to 6 halogen substituted
alkyl, such as trifluoromethyl.
[0008] The term "C.sub.1-C.sub.6alkyl", as used herein, unless
otherwise indicated, includes 1 to 6 saturated monovalent
hydrocarbon radicals having straight or branched moieties,
including, but not limited to, methyl, ethyl, n-propyl, iso-propyl,
n-butyl, sec-butyl, tert-butyl, and the like.
[0009] The term "C.sub.1-C.sub.6alkoxy", as used herein, unless
otherwise indicated, includes --OC.sub.1-C.sub.6alkyl groups
wherein C.sub.1-C.sub.6alkyl is as defined above, such as methoxy
and ethoxy.
[0010] The term "cyano", as used herein, unless otherwise
indicated, includes --C--N.
[0011] The term "nitro", as used herein, unless otherwise
indicated, includes --NO.sub.2.
Methods of Preparation
[0012] The present invention relates to a process for preparing
6-(7-((1-aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-
-naphthamide (AL3810) by deprotection of substituted benzyl
1-((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quinolin-7-yloxy)--
methyl)cyclopropylcarbamate Formula I under a diluted or weak
acidic condition according to Process A.
Process A
##STR00002##
[0013] Wherein
[0014] R.sub.1 is selected from H, halogen,
halogeno-C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, cyano or nitro; R.sub.2 is selected from
C.sub.1-C.sub.6alkoxy, or nitro.
[0015] The present invention relates to the compound of Formula
I.
[0016] The present invention relates to the methods of preparing a
compound having the Formula I.
[0017] The present invention also relates to various intermediates
useful in the preparation of a compound having the Formula I, and
the present invention further relates to the methods of preparing
such intermediates.
[0018] The present invention relates to the methods of preparing a
crystalline form of
6-(7-((1-aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-
-naphthamide.
DESCRIPTION OF DRAWINGS
[0019] FIG. 1 provides a H1 nuclear magnetic resonance (NMR) graph
of a crystalline form of
6-(7-((1-aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-
-naphthamide.
[0020] FIG. 2 provides a differential scanning calorimetric (DSC)
graph of a crystalline form of
6-(7-((1-aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-
-naphthamide.
[0021] FIG. 3 provides a thermogravimetric analysis (TGA) graph of
a crystalline form of
6-(7-((1-aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-
-naphthamide.
[0022] FIG. 4 provides an X-ray powder diffraction (XRPD) graph of
a crystalline form of
6-(7-((1-aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-
-naphthamide.
DETAILED DESCRIPTION OF THE INVENTION
[0023] The present invention relates to a process for preparing
6-(7-((1-aminocyclo-propyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl--
1-naphthamide (AL3810) by deprotection of substituted benzyl
1-((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quinolin-7-yloxy)--
methyl)cyclopropylcarbamate Formula I under a diluted or weak
acidic condition according to above Process A.
Wherein
[0024] R.sub.1 is selected from H, halogen,
halogeno-C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, cyano or nitro; preferably selected from H,
C.sub.1-C.sub.6alkoxy, or nitro; R.sub.2 is selected from
C.sub.1-C.sub.6alkoxy, or nitro; preferably R.sub.2 is methoxy. A
diluted or weak acidic condition is selected from 5-50% TFA in
CH.sub.2Cl.sub.2 or CH.sub.3CN, 10% HCl in ethanol, 4NHCl in
dioxane, HCOOH in CH.sub.3CN or p-toluenesulfonic acid monohydrate
in CH.sub.3CN; preferably the acid is 10% TFA in
CH.sub.2Cl.sub.2.
[0025] The total volume ratio of solvent to reactant is from 2 to
20 folds by weight. The reaction temperature is selected from 0 to
80.degree. C. and the reaction time is selected from 0.5 to 24
hours.
[0026] A preferred procedure is shown in Scheme I.
[0027] The present invention relates to a process for preparing
6-(7-((1-aminocyclo-propyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl--
1-naphthamide (AL3810) by deprotection of 4-methoxybenzyl
1-((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)-quinolin-7-yloxy)-
-methyl)cyclopropylcarbamate Formula II according to Process B.
Process B
##STR00003##
[0029] The present invention relates to the compound of Formula
II.
[0030] The present invention relates to the methods of preparing a
compound having the Formula II.
[0031] The present invention also relates to various intermediates
useful in the preparation of a compound having the Formula II, and
the present invention further relates to the methods of preparing
such intermediates.
[0032] Process B of the invention comprises preparing AL3810, a
preferred procedure is shown in Scheme II via:
(a) under a condition of 10% TFA in CH.sub.2Cl.sub.2, preferably at
0.degree. C. to 50.degree. C. for 3-10 hours with 5-20 folds volume
of 10% TFA in CH.sub.2Cl.sub.2 as the solvent, or (b) under a
condition of 2-4 eq TSA.H.sub.2O, preferably at room temperature to
80.degree. C. for 10-24 hours with CH.sub.3CN as the solvent.
[0033] The present invention relates to a compound of Formula I or
Formula II and the method preparing Formula I or Formula II
according to Process C.
Process C
##STR00004##
##STR00005##
[0034] Wherein
[0035] R.sub.1 is selected from H, halogen,
halogeno-C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, cyano or nitro; R.sub.2 is selected from
C.sub.1-C.sub.6alkoxy, or nitro.
[0036] Process C of the invention comprises preparing Formula I, a
preferred procedure is shown in Scheme III via the reaction between
formula 14 and Formula VI using a base, such as: Na.sub.2CO.sub.3,
Cs.sub.2CO.sub.3 or K.sub.2CO.sub.3, or between formula 14 and
Formula V using a base, such as: Na.sub.2CO.sub.3, Cs.sub.2CO.sub.3
or K.sub.2CO.sub.3, and KI or NAI to give Formula I, preferably the
reaction is at a heated condition, such as 60-120.degree. C. in
acetone, DMF or NMP.
[0037] Formula 14 can be prepared by following steps:
(a) A direct acylation of formula 10 without any protection by
methylamine hydrochloride with heat pre-activation of formula 10 at
the presence of CDI gives formula 11, preferably the reaction is
carried out in DMF or dioxane for 2-8 hours with 1.5-4 eq CDI at a
heated condition, such as at 50-120.degree. C., (b) (i) Coupling
formula 11 with formula 12 (WO2008112408) at 100-160.degree. C. in
lutidine, such as 1,6-lutidine, or pyridine with 1.5-3 eq DMAP for
2-24 hours gives formula 13, or
[0038] (ii) Coupling formula 11 with formula 12 under similar
Ullmann reaction conditions, such as: a base, CuI and 2-picolinic
acid gives formula 13, preferably a base is one of
Na.sub.2CO.sub.3, Cs.sub.2CO.sub.3 and K.sub.2CO.sub.3, CuI amount
is catalytic amount at 1-50% eq and 2-piclinic acid is at 1-50% eq.
The reaction is at 100-160.degree. C. in DMF or NMP for 10-36
hours, or
[0039] (iii) Coupling formula 11 with formula 12 under similar
Ullmann reaction conditions, such as: a base, CuI and pentanedione
gives formula 13, preferably a base is one of Na.sub.2CO.sub.3,
Cs.sub.2CO.sub.3 and K.sub.2CO.sub.3, CuI amount is catalytic
amount at 1-50% eq and pentanedione is 1,4-pentanedione. The
reaction is at 100-160.degree. C. in DMF or NMP for 10-36
hours.
(c) Deprotecting formula 13 with TFA gives formula 14 as a TFA
salt, preferably at 60-100.degree. C. for 0.5-8 hours.
[0040] Formula VI or Formula V can be prepared by following
steps:
(d) Reacting formula 15 with R.sub.1, R.sub.2 substituted benzyl
alcohol with DPPA and triethylamine gives Formula III, preferably
using 2-4 eq DPPA and 2-4 eq TEA in toluene or dioxane at a heated
condition for 10-28 hours through Curtis rearrangement. (e)
Reducting Formula III by NaBH.sub.4 gives Formula IV, preferably at
reflux condition in THF with addition of methanol. (f) Reacting
Formula IV with CH.sub.3SO.sub.2Cl gives Formula V, preferably in a
basic condition at -10.degree. C.-25.degree. C. (g) Reacting
Formula V with KI or NaI gives Formula VI, preferably refluxing in
acetone or acetonitrile. This step can be modified as one pot
reaction without isolation as Scheme III described.
[0041] Process C of the invention comprises preparing Formula II, a
preferred procedure is shown in Scheme IV via the reaction between
formula 14 and formula 15f using a base, such as: Na.sub.2CO.sub.3,
Cs.sub.2CO.sub.3 or K.sub.2CO.sub.3, or between formula 14 and
formula 15d using a base, such as: Na.sub.2CO.sub.3,
Cs.sub.2CO.sub.3 or K.sub.2CO.sub.3, and KI or NaI at a heated
condition, such as at 60-120.degree. C. of one pot reaction in
acetone, DMF or NMP to give Formula II.
[0042] The present invention relates to the compound of Formula I
and the method preparing Formula I according to Process D.
Process D
##STR00006##
[0044] Process D of the invention comprises preparing Formula I, a
preferred procedure is shown in Scheme V via acylazide formula 17
reacting with R.sub.1, R.sub.2 substituted benzyl alcohol in a
heated condition, preferably toulene or dioxane refluxing
condition.
[0045] Formula 17 can be prepared by reacting formula 16 with ethyl
chloroformate at 0.degree. C. in DMF or THF at the presence of TEA
or DIPEA to form a mixed anhydride that can be reacted with
NaN.sub.3/DMF solution at similar temperature. Formula 16 can be
prepared according to WO2008112408.
[0046] The present invention relates to the compound of Formula I
and the method preparing Formula I according to Process E.
Process E
##STR00007##
[0047] Wherein
[0048] R.sub.1 is selected from H, halogen,
halogeno-C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, cyano or nitro; R.sub.2 is selected from
C.sub.1-C.sub.6alkoxy, or nitro.
[0049] Process E of the invention comprises preparing Formula I, a
preferred procedure is shown in Scheme VI via acylation of Formula
VIII with methylamine hydrochloride with heat pre-activation of
formula VIII at the presence of CDI gives Formula I, preferably the
reaction is carried out in DMF or dioxane for 2-8 hours with 1.5-4
eq CDI at 50-120.degree. C. Formula VII can be similarly prepared
by reacting formula 19 with Formula VI with a base, such as:
Na.sub.2CO.sub.3, Cs.sub.2CO.sub.3 or K.sub.2CO.sub.3, or with
Formula V in one pot KI or NaI with a base, such as:
Na.sub.2CO.sub.3, Cs.sub.2CO.sub.3 or K.sub.2CO.sub.3, as described
in Scheme III. Formula VIII can be prepared by hydrolysis of
Formula VII under a strong basic condition, such as a mixture of an
aqueous NaOH solution and EtOH. Formula 19 can be prepared
according to WO2008112408 from formula 18.
[0050] The present invention relates to the compound of Formula I
or Formula II and the method preparing Formula I or Formula II
according to Process F.
Process F
##STR00008##
##STR00009##
[0051] Wherein
[0052] R.sub.1 is selected from H, halogen,
halogeno-C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, cyano or nitro; R.sub.2 is selected from
C.sub.1-C.sub.6alkoxy, or nitro.
[0053] Process F of the invention comprises preparing Formula I, a
preferred procedure is shown in Scheme VII via:
(a) Coupling formula 11 with Formula IX at 100-160.degree. C. in
lutidine, such as 1,6-lutidine, or pyridine with 1.5-3 eq DMAP for
2-24 hours gives Formula I, or (b) coupling formula 11 with Formula
IX under similar Ullmann reaction conditions, such as: a base of
Na.sub.2CO.sub.3, Cs.sub.2CO.sub.3 and K.sub.2CO.sub.3 with
catalytic amount of CuI (1-50% eq) and 2-piclinic acid (1-50% eq)
at 100-160.degree. C. in DMF or NMP for 10-36 hours gives Formula
I, or (c) coupling formula 11 with Formula IX under similar Ullmann
reaction conditions, such as: a base of Na.sub.2CO.sub.3,
Cs.sub.2CO.sub.3 and K.sub.2CO.sub.3 with catalytic amount of CuI
(1-50% eq) and pentanedione (1-50% eq), such as 1,4-pentanedione,
at 100-160.degree. C. in DMF or NMP for 10-36 hours gives Formula
I.
[0054] Formula IX can be prepared by reacting Formula IV with
formula 21 under Mitusnobu reaction condition in THF at
0-40.degree. C. for 2-24 hours by use of Mitusnobu reagents, such
as: DEAD or DIAD at the presence of a Mitsunobu ligand, such as
triphenylphosphine. Formula 21 can be prepared by deprotection of
formula 20 with TFA at 60-100.degree. C. for 0.5-8 hours to give a
TFA salt that can be neutralized by aqueous NaHCO.sub.3 solution,
and then filtered off.
[0055] Process F of the invention comprises preparing Formula II, a
preferred procedure is shown in Scheme VIII via:
(a) Coupling formula 11 with formula 21b at 100-160.degree. C. in
lutidine, such as 1,6-lutidine, or pyridine with 1.5-3 eq DMAP for
2-24 hours gives Formula II, or (b) coupling formula 11 with
formula 21b under similar Ullmann reaction conditions, such as: a
base of Na.sub.2CO.sub.3, Cs.sub.2CO.sub.3 and K.sub.2CO.sub.3 with
catalytic amount of CuI (1-50% eq) and 2-picolinic acid (1-50% eq)
at 100-160.degree. C. in DMF or NMP for 10-36 hours gives Formula
II, or (c) coupling formula 11 with formula 21b under similar
Ullmann reaction conditions, such as: a base of Na.sub.2CO.sub.3,
Cs.sub.2CO.sub.3 and K.sub.2CO.sub.3 with catalytic amount of CuI
(1-50% eq) and pentanedione (1-50% eq), such as 1,4-pentanedione,
at 100-160.degree. C. in DMF or NMP for 10-36 hours gives Formula
II.
[0056] Formula 21b can be prepared by reacting formula 15c with
formula 21 under Mitusnobu reaction condition in THF at
0-40.degree. C. for 2-24 hours with use of Mitsunobu reagents, such
as: DEAD or DIAD, at the presence of a Mitsunobu ligand, such as
triphenylphosphine.
[0057] The present invention relates to the methods of preparing a
crystalline form of
6-(7-((1-aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-
-naphthamide (AL3810) by recrystallizing the crude product from
isopropanol to give a stable crystalline form. The crude product
was dissolved at refluxing condition for 15 minutes to 3 hours in
isopropanol with certain amount of active carbon. The reaction was
filtered at hot condition and cooled to room temperature
(optionally cooled at 4.degree. C.) for 4 to 48 hours. The
precipitate was filtered and dried under high vacuum at 25.degree.
C.-80.degree. C. to give a stable crystalline form with melting
point at 185.degree. C.-205.degree. C. The crystalline form has no
observable endotherm from about 40.degree. C. to about 185.degree.
C. as determined by DSC. It has observable endotherm from about
185.degree. C. to about 210.degree. C. as determined by DSC. The
crystalline form has a TGA themogram that doesn't exhibit
significant weight loss until at 210.degree. C. to 250.degree. C.
to indicate that it is an unsolvated material. The crystalline form
has 20-40 characteristic peaks on XRPD graph.
[0058] The following examples further illustrate the present
invention, but should not construed as in any way to limit its
scope.
Example 1
Representation of Process A and Process B
Process for preparation of
6-(7-((1-aminocyclopropyl)methoxy)-6-methoxy-quinolin-4-yloxy)-N-methyl-1-
-naphthamide (AL3810)
[0059] To a stirred mixture of 4-methoxybenzyl
1-((6-methoxy-4-(5-(methylcarbamoyl)-naphthalen-2-yloxy)-quinolin-7-yloxy-
)methyl)cyclopropylcarbamate Formula II (150 g) in DCM (1.5 L) was
added TFA (150 ml) through an additional funnel for about 30 min at
RT. The reaction was stirred at 30.degree. C. for 4 hours and added
into water (3 L). The aqueous layer was extracted with DCM twice
(1.5 L.times.2) and basified with 3N NaOH (620 ml) to adjust pH
11-12 with a fine white solid precipitation. The solid was filtered
and washed with water, further suction dry. The solid was dissolved
into a mixture of chloroform/methanol (5 L, 3.5 L/1.5 L) and
further washed with brine (2 L). It was dried with MgSO.sub.4 and
filtered. The solution was evaporated with EtOAc (2 L) three times
to a slurry solution and cooled to RT. It was filtered and the
filter cake was washed with ether, further air dried to give the
crude titled compound 105 g, yield: 95.9%. MS: (M+1) 444.
Example 2
Representation of Process A and Process B
Process for preparation of
6-(7-((1-aminocyclopropyl)methoxy)-6-methoxy-quinolin-4-yloxy)-N-methyl-1-
-naphthamide (AL3810)
[0060] To a stirred mixture of 4-methoxybenzyl
1-((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)-quinolin-7-yloxy)-
methyl)cyclopropylcarbamate Formula II (1 g) in ACN (15 ml) was
added TSA.H.sub.2O (3 eq). The reaction was stirred at RT for 24
hours and it was basified with 3N NaOH. The solution was extracted
with DCM three times, washed with brine and dried with MgSO4. The
solution then was filtered and evaporated, further recrystalized
from IPA to give pure titled compound 550 mg, yield: 75%. MS: (M+1)
444.
Example 3
Representation of Process C
Process for preparation of 4-methoxybenzyl
1-((6-methoxy-4-(5-(methylcarbamoyl)-naphthalen-2-yloxy)-quinolin-7-yloxy-
)methyl)cyclopropylcarbamate Formula II
##STR00010##
[0062] To a stirred mixture of 6-hydroxy-1-naphthoic acid (19 g,
formula 10) in DMF (150 ml) was added CDI (22 g). The reaction was
heated at 80.degree. C. for 30 min and CH.sub.3NH.sub.2.HCl (40 g)
was added into the reaction. The reaction was heated for 3 hours at
80.degree. C. and cooled to RT and further diluted with water (300
ml). It was acidified with 1N HCl to pH 2-3 and extracted three
times with EtOAc (150 ml). The combined organic layer was washed
with saturated NaHCO.sub.3 solution followed by water and brine.
The solution was dried with Na.sub.2SO.sub.4 and evaporated to give
the 4-hydroxy-N-methyl-naphamide formula 11 compound 12 g.
##STR00011##
[0063] (i) To a mixture of formula 11 (6.5 g), formula 12 (6.5 g)
and DMAP (5.5 g) was added 1,6-lutidine (20 ml). The reaction was
stirred and heated at 135.degree. C. for 5 hours from heterogeneous
to homogeneous. The reaction was cooled and IPA (35 ml) was added
into the reaction under slow stirring for 2 hours at RT. The solid
was filtered and further washed with IPA, dried to give the formula
13 compound 5.8 g as a gray solid, yield 57%, or
[0064] (ii) To a mixture of formula 11 (500 mg), formula 12 (500
mg), CuI (80 mg), Cs.sub.2CO.sub.3 (1 g) and 1-picolinic acid (150
mg) was added DMF (0.5 ml). The reaction was stirred and heated at
120.degree. C. for 24 hours. It was directed loaded on silica gel
column to purify to give the formula 13 compound 370 mg, yield 48%,
or
[0065] (iii) To a mixture of formula 11 (500 mg), formula 12 (500
mg), CuI (80 mg), Cs.sub.2CO.sub.3 (1 g) and 2,4-pentanedione (10
mg) was added DMF (0.5 ml). The reaction was stirred and heated at
120.degree. C. for 24 hours. It was directed loaded on silica gel
column to purify to give the formula 13 compound 450 ma, yield
58%.
##STR00012##
[0066] A mixture of formula 13 (5.8 g) and TFA (12 ml) was heated
at 90.degree. C. for one hour. The reaction was evaporated under
reduced pressure and triturated with EtOAc. The solid was filtered
and washed with EtOAc twice to give formula 14 as a TFA salt 5.5 g,
yield 95%.
##STR00013##
[0067] To a mixture of acid-ester (8.2 g, formula 15) and
4-methoxybenzyl alcohol (9.5 g) in toluene (50 ml) was added DPPA
(15 g), the reaction was stirred and TEA was added into the
reaction through an additional funnel at RT. The reaction then was
refluxed for 20 hours and cooled to RT. To the reaction was added
2N NaOH (30 ml) and followed by extraction with EtOAc three times.
The combined organic layer was washed with water to neutral and
dried with Na.sub.2SO.sub.4. The solution was filtered and
evaporated followed by addition of EtOAc/PE (petroleum ether) and
stored in a refrigerator overnight. The crystals were filtered and
washed with cold EtOAc/PE to give an off white powder. The product
formula 15b was vacuum oven dried at 30.degree. C. to give 8.0 g as
ethyl 1-((4-methoxybenzyloxy)carbonylamino)cyclopropanecarboxylate
(formula 15b), yield: 53%. MS: (M+1) 294.
##STR00014##
[0068] To a mixture of formula 15b (8.0 g) and THF (50 ml) was
added NaBH.sub.4 (8 g). The reaction was refluxed for 12 hours.
Methanol (15 ml) was slowly added to the reaction and refluxed for
4 hour. The solvent was evaporated and cooled. NH.sub.4Cl (6.3 g)
and water (60 ml) were added and stirred. The mixture was extracted
with DCM three times and dried with Na.sub.2SO.sub.4. The solution
was filtered and evaporated followed by addition of ethanol to
recrystalize overnight. The crystal was filtered to give an off
white powder and further dried in oven to give the product 4.0 g as
4-methoxybenzyl 1-(hydroxymethyl)cyclopropylcarbamate (formula
15c), yield: 58%. MS: (M+1) 252.
##STR00015##
[0069] To a stirred mixture of formula 15c (100 g) and DCM (400 ml)
was added DIPEA (78 g). The result solution was cooled to
0-5.degree. C. with ice/water and further stirred under this
temperature for 15 min. MsCl (60 g) was added via an addition
funnel dropwise keeping temperature below 5.degree. C. for about
1.5 hours. After completion of addition, the reaction mixture was
allowed stirring at 0-5.degree. C. for 30 min and quenched with
saturated NaHCO.sub.3 (300 ml). The solution was extracted with 200
ml DCM twice. The combined DCM layer was washed with 0.1 N HCl (400
ml) followed by brine. It was dried over Na.sub.2SO.sub.4 and
concentrated to obtain an off-white solid 123 g of formula 15d, MS:
(M+1) 330.
##STR00016##
[0070] To a stirred mixture of formula 15d (3.3 g) and KI (3.3 g)
was added acetone (30 ml), the reaction was refluxed for 2 hours
and cooled. The reaction was evaporated and extracted with EtOAc
(30 ml) twice and washed with brine, further evaporated under
reduced pressure to give the crude product 2.3 g of formula 15e,
MS: (M+1) 362.
##STR00017##
Method A:
[0071] To a stirred mixture of formula 14 (500 mg), formula 15d
(450 mg), K.sub.2CO.sub.3 (400 mg) and NaI (180 mg) was added
acetone (10 ml), the reaction suspension was heated to reflux for
20 hours as one pot reaction. The reaction was evaporated and
purified on silica gel column to give the product 510 mg of Formula
II. MS: (M+1) 608. .sup.1H NMR (DMSO-d6): .delta.: 8.53-8.54 (m,
2H), 8.37-8.39 (d, 1H), 8.00-8.02 (d, 1H), 7.83-7.88 (m, 2H),
7.53-7.61 (m, 4H), 7.42 (s, 1H), 7.22-7.24 (d, 2H), 6.83-6.85 (d,
2H), 6.61-6.62 (d, 1H), 4.91 (s, 2H), 4.23 (s, 2H), 3.95 (s, 3H),
3.70 (s, 3H), 2.86-2.87 (d, 3H), 0.83-0.93 (d, 4H).
Method B:
[0072] To a stirred mixture of formula 14 (500 mg), formula 15e
(500 mg) and K.sub.2CO.sub.3 (400 mg) was added acetone (10 ml),
the reaction suspension was heated to reflux for 20 hours. The
reaction was evaporated and purified on silica gel column to give
the product 560 mg of Formula II. MS: (M+1) 608. .sup.1H NMR
conforms to Formula II from above Method A.
Method C:
[0073] To a stirred mixture of formula 14 (33 g), formula 15d (43
g), K.sub.2CO.sub.3 (41 g) and KI (16.6 g) was added acetone (400
ml). The reaction suspension was heated to reflux for about 30 hr.
The reaction was concentrated and to the residue was added water
(700 ml). The result suspension was stirred for 1 hour slowly to
get a brown solid. The solid was filtered and rinsed with water
twice further rinsed with ethanol. The crude product was dried in
oven at 40.degree. C. for 2-3 hours. The product was purified with
IPA by recrystalization to give 29 g of Formula II. MS: (M+1) 608.
.sup.1H NMR conforms to Formula II from above Method A.
Example 4
Representation of Process D
Process for preparation of 4-methoxybenzyl
1-((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)-quinolin-7-yloxy)-
methyl)cyclopropyl-carbamate Formula II
[0074] A mixture of
2-(1-((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quino-lin-7-ylo-
xy)methyl)cyclopropyl)acetyl azide formula 17 (WO2008112408, 150
mg) and 4-methoxybenzyl alcohol (0.15 ml) in toluene (10 ml) was
refluxed for 1.5 hour. The reaction was evaporated and purified
with silica gel column to give the titled product. Mass: (M+1),
608
Example 5
Representation of Process E
Process for preparation of 4-methoxybenzyl
1-((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)-quinolin-7-yloxy)-
methyl)cyclopropylcarbamate Formula II
##STR00018##
[0076] A mixture of 6-Hydroxy-1-naphthoic acid (1 g) and
H.sub.2SO.sub.4 (0.2 ml) in EtOH (25 ml) was refluxed overnight and
evaporated, followed by dissolving into EtOAc. The solution was
washed with water, IN NaHCO.sub.3 solution and brine, further dried
by Na.sub.2SO.sub.4. The solution was evaporated to give crude
ethyl 6-hydroxy-1-naphthoate 0.9 g which was reacted with formula
12 at similar preparation conditions to formula 13 of Example 3 to
give the above product of formula 18. Formula 19 was similarly
prepared to formula 14 of Example 3.
[0077] A reaction between formula 19 and formula 15d similarly to
the preparation of Formula II of Method A gave ethyl
6-(6-methoxy-7-((1-((4-methoxybenzyloxyl)carbonylamino)cyclopropyl)methox-
y)quinolin-4-yloxy)-1-naphthoate which was hydrolyzed with 10% NaOH
in EtOH at RT to give
6-(6-methoxy-7-((1-((4-methoxybenzyloxy)carbonylamino)cyclopropyl)methoxy-
)-quinolin-4-yloxy)-1-naphthoic acid. The resulting acid was
acylated similarly to the preparation of formula 11 of Example 3
with CH.sub.3NH.sub.2.HCl under the heat pre-activation at the
presence of CDI to give the titled product.
Example 6
Representation of Process F
Process for preparation of 4-methoxybenzyl
1-((6-methoxy-4-(5-(methylcarbamoyl)-naphthalen-2-yloxy)-quinolin-7-yloxy-
)methyl)cyclopropylcarbamate Formula II
##STR00019##
[0079] To a mixture of 4-chloro-6-methoxyquilolin-7-ol (formula 21,
5.2 g),
1-((4-methoxybenzyloxy)carbonylamino)cyclopropanecarboxylate
(formula 15b, 8.3 g) and triphenylphosphine (9.8 g) in THF (250 ml)
was added DEAD (6.5 g) dropwise at RT in 1.5 hours, the reaction
was further stirred for 20 hours at RT and evaporated. The residue
was purified with silica gel column to give the 4-methoxybenzyl
1-((4-chloro-6-methoxy-quinolin-7-yloxy)methyl)cyclopropylcarbamate
formula 21b product 6.5 g.
[0080] The titled compound of Formula II was then similarly
prepared by using formula 21b to react with
4-hydroxy-N-methyl-naphamide formula 11 according to formula 13 of
Example 3.
Example 7
Preparation of the crystalline form of
6-(7-((1-aminocyclopropyl)methoxy)-6-methoxy-quinolin-4-yloxy)-N-methyl-1-
-naphthamide (AL3810)
[0081] The crude product from Example 1 (105 g) was mixed with
isopropanol (2.5 L) and active carbon (5 g), the mixture was heated
to reflux for 0.5 hour to dissolve all crude product followed by
filtration while it was hot, then the filtrate was refluxed again
for 10 minutes and it was cooled to room temperature overnight
under a slow stirring condition. The precipitate was filtered and
washed with ethyl ether (500 ml.times.2), further dried under high
vacuum at 80.degree. C. to give the pure product (85 g) with
melting point at 192.degree. C.-196.degree. C.
H1 NMR shown in FIG. 1. DSC shown in FIG. 2 having observable
endotherm from about 193.degree. C.-202.degree. C. TGA shown in
FIG. 3 demonstrating as an unsolvated material with weight loss at
about 230.degree. C. XRPD shown in FIG. 4 having pattern
compromising thirty three characteristic peaks with all intensity
and intensity % expressed in d values and angles as follows:
TABLE-US-00001 NO. Angle d value 1 10.429 8.476 2 11.811 7.487 3
12.287 7.198 4 13.293 6.655 5 13.658 6.478 6 15.778 5.612 7 16.186
5.472 8 16.682 5.310 9 17.102 5.181 10 17.907 4.949 11 18.631 4.759
12 19.027 4.661 13 19.847 4.470 14 20.545 4.320 15 21.214 4.185 16
21.843 4.066 17 22.058 4.026 18 22.682 3.917 19 23.453 3.790 20
24.065 3.695 21 24.708 3.600 22 25.072 3.549 23 25.435 3.499 24
25.886 3.439 25 27.929 3.192 26 28.420 3.138 27 29.137 3.062 28
30.331 2.944 29 31.172 2.867 30 31.803 2.811 31 32.613 2.743 32
37.959 2.369 33 39.470 2.281
And
[0082] H1 NMR shown in FIG. 1. DSC shown in FIG. 2 having
observable endotherm from about 193.degree. C.-202.degree. C. TGA
shown in FIG. 3 demonstrating as an unsolvated material with weight
loss at about 230.degree. C. XRPD shown in FIG. 4 having pattern
compromising characteristic peaks with intensity % greater than 10%
expressed in d values and angles as follows:
TABLE-US-00002 NO. Angle d value 1 10.429 8.476 4 13.293 6.655 6
15.778 5.612 7 16.186 5.472 10 17.907 4.949 12 19.027 4.661 13
19.847 4.470 15 21.214 4.185 16 21.843 4.066 17 22.058 4.026 18
22.682 3.917 19 23.453 3.790 20 24.065 3.695 21 24.708 3.600 22
25.072 3.549 23 25.435 3.499 25 27.929 3.192 31 32.613 2.743 33
39.470 2.281
* * * * *